Protein-based therapies can be more difficult to administer to patients than other pharmaceuticals. Because the efficacy of a protein is related to its conformation, therapeutic formulations cannot be subjected to conditions that contribute to the unfolding, or denaturing, of the protein. Special care is typically used in preparing, storing, and administering protein-based therapies. In addition to avoiding any denaturing of the protein, it is often desirable to control the amount of the protein administered to a patient over time. This helps to avoid protein concentrations within the patient that are undesirably high or that are too low to be effective. Controlled release protein-based therapies can be administered by a variety of methods, including oral delivery of tablets or capsules, inhalation of powders, and implantation of depots from which the protein is gradually released.
The preparation of these formulations typically includes mixing the protein with an organic solvent. For example, a powder formulation may be made by spraying a mixture of the protein and an organic solvent into liquid nitrogen. Alternatively, the protein may be mixed with a solution of a bioerodible polymer in an organic solvent, with formation of microparticles which contain the protein and the polymer by coagulation of the mixture. Furthermore, proteins, powdered formulations, or microparticles can be mixed with an organic solvent to produce a liquid or gel which may be injected into a patient. A drawback to the use of organic solvents is their tendency to cause protein denaturing.
Additives have been used to stabilize proteins in the presence of a denaturing organic solvent. These additives include surfactants (U.S. Pat. No. 5,096,885), amino acids (U.S. Pat. No. 4,297,344), polyols (U.S. Pat. No. 5,589,167), natural polymers (WO 8903671), synthetic polymers (Pharm. Res. 8:285–291, 1991), and metals (U.S. Pat. No. 6,191,107 B1).
There is a need for improved stabilization of proteins during the preparation, storage, and administration of protein-based therapies. Protein formulations which have good stability in organic solvents would be useful in a wide variety of controlled release applications.